Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson's disease

Treatment of Parkinson's disease (PD) with levodopa or dopamine agonists often produces psychotic side effects, including delusions and hallucinations, particularly visual hallucinations. ^[1] Sleep disorders often precede these symptoms. Such psychotic disturbances affect up to 80% of patients with concomitant dementia and 20% of patients without concomitant dementia. ^[1]

Drug-induced psychoses are due to over-stimulation of mesolimbic dopamine receptors. ^[1] Hence, these symptoms should be treatable by reducing the dose of antiparkinsonian drug or by using antipsychotic agents, which act as dopamine antagonists. Withdrawal or reduction of dopaminomimetic drugs, however, can exacerbate the motor symptoms of PD, ^[2] whereas conventional antipsychotics, such as chlorpromazine, are associated with a significant risk of extrapyramidal adverse effects that may lead to further deterioration of parkinsonism. ^[1] Atypical antipsychotics, such as clozapine, are associated with a lower risk of extrapyramidal effects and thus may be suitable for the treatment of drug-induced psychosis in patients with PD. Several studies have shown that these agents improve psychotic symptoms in parkinsonian patients. ^[3-6] Clozapine and remoxipride, however, can produce marked leukopenia, ^[1] whereas risperidone and remoxipride, as with conventional antipsychotics, do have extrapyramidal side effects. ^[6,7]

Olanzapine is an atypical antipsychotic with a high affinity for dopaminergic and serotonergic receptors. ^[8] Its clinical profile is comparable with that of clozapine, ^[8] but, in contrast to clozapine, it does not produce granulocytopenia. ^[1] This paper describes the effects of olanzapine on drug-induced psychosis in nondemented patients with PD.

Methods.

The trial was an open study involving 15 patients (9 men, 6 women) with PD (defined according to the UK Brain Bank criteria) and drug-induced dopaminomimetic psychosis (defined according to DSM-IV criteria) without dementia. No patients were receiving adjunctive treatment with anticholinergic agents or amantadine. Informed consent was obtained from all patients or their legal representatives.

After an initial period during which the dose of dopaminomimetic medication was titrated down to the lowest acceptable dose, which had to remain stable for at least 5 days, treatment with olanzapine (given once daily, in the evening) was started at an initial daily dose of 1 mg orally. The dose was then titrated to the optimum dose between day 8 and day 50; the maximum permissible dose was 15 mg/day. Patients were challenged with higher doses of dopaminomimetic agents from day 50 to day 64 in order to reduce parkinsonian motor symptoms. Patients were assessed weekly by means of the Brief Psychiatric Rating Scale (BPRS), the Unified PD Rating Scale (UPDRS), and sleep somnologue. The sleep somnologue was a timetable used to record sleep over 24 hours, which was completed by the patients or their care-givers; total sleep time was defined as the time spent sleeping between 2100 and 0900 hours. Vital signs, laboratory tests, and adverse events were also monitored weekly.

Differences between male and female patients were tested for statistical significance by means of the Mann-Whitney test. Changes in BPRS, UPDRS, and appropriate subscales on days 1, 8, 50, and 64 were tested by means of Wilcoxon's signed rank test.

Results.

The mean age of the patients was 66.5 +/- 11.4 years, and the mean duration of the disease was 10.7 +/- 6.8 years. Their mean daily medication was 6.45 +/- 3.56 dopaminomimetic units (1 unit = 100 mg levodopa, 10 mg bromocriptine, or 1 mg pergolide). All patients were treated with levodopa, the mean daily dose being 503.3 +/- 225.6 mg on day 1, 410 +/- 190.1 mg between days 8 and 50, and 725 +/- 329.2 mg on day sixty-four. Eight patients were co-treated with pergolide, at mean daily doses of 2.2 +/- 1.4 mg on day 1, 2.0 +/- 1.1 mg on days 8 to 50, and 2.4 +/- 0.9 mg on day 64; one patient received bromocriptine, 40 mg on day 1, 20 mg on days 8 to 50, and 20 mg on day 64, at the same time as levodopa. Male and female patients were well matched with regard to age, duration of PD, medication received, and baseline BPRS and UPDRS scores. The only significant difference was slightly higher BPRS core symptoms (conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content) score in male patients (mean score 9.0 +/- 2.6 compared to 5.2 +/- 2.9 in women; p < 0.05). Persecutory delusions were present in 13 patients, one of whom also had delusions of being poisoned. Visual hallucinations occurred in 13 patients, of whom two also experienced auditory hallucinations. Two patients had previously been treated unsuccessfully with clozapine. The final daily dose of olanzapine ranged from 2 to 15 mg (mean, 6.5 +/- 3.9 mg); this is lower than the range normally used in schizophrenia (5 to 20 mg/d).

(Table 1) shows BPRS and UPDRS scores on day 1, day 8 (after titration to the lowest dose of dopaminomimetic medication), day 50 (after titration to the optimal dose of olanzapine), and day 64 (after dopaminomimetic challenge). Olanzapine treatment significantly reduced BPRS total scores by 65% and core symptom subscores by 67% in 14 patients (see Table 1, Figure 1), including the two who had previously shown no response to clozapine. This reduction in psychotic symptoms appeared within 2 to 5 weeks. One patient died as a result of complications of orthopedic surgery that were unrelated to the study drug. There were no significant changes in UPDRS total scores or Activities of Daily Living (ADL) and motor symptom subscores during olanzapine dose titration (see Table 1, Figure 2).

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Figure 1. BPRS total scores as well as core symptom and negative symptom subscores in relation to mean doses of dopaminomimetic agents. Scores are expressed as percentages of the maximum attainable value for each scale; mean doses of dopaminomimetic agents are expressed as units (1 unit = 100 mg levodopa, 10 mg bromocriptine, or 1 mg pergolide). *p < 0.05 compared with values at days 1 and 8; **p < 0.05 compared with values at days 1, 8, and 50.

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Figure 2. UPDRS total scores, and Activities of Daily Living (ADL) and motor symptom subscores in relation to mean doses of dopaminomimetic agents. Scores are expressed as percentages of the maximum attainable value for each scale; mean doses of dopaminomimetic agents are expressed as units (1 unit = 100 mg levodopa, 10 mg bromocriptine, or 1 mg pergolide). **p < 0.05 compared with values at days 1, 8, and 50.

During dopaminomimetic challenge (days 50 to 64), all 14 patients showed significant reductions in UPDRS total scores as well as ADL and motor symptom subscores (see Table 1, Figure 2). One patient showed a transient increase in BPRS scores during this phase, which was adequately treated by increasing the dose of olanzapine. However, this patient discontinued treatment because of drowsiness. In the other 13 patients, the mean reduction in UPDRS, when compared to scores on day 8 (day 50), was 21% (18%), the mean reduction in ADL was 13% (16%), and the mean reduction in motor symptom subscores was 15% (19%) (p < 0.01 in each case). BPRS total scores in these 13 patients remained significantly reduced by 67%, and core symptom subscores remained significantly reduced by 77% when compared to day 8 (see Table 1, Figure 1).

Olanzapine induced a significant increase in total sleep time (45%; p < 0.01). The quality of sleep is usually impaired in patients with PD, and hence this increased sleep was welcomed by most patients. No other side effects or changes in safety measures, vital signs, or laboratory tests were observed. In particular, there was no increase in drowsiness, a common dose-limiting effect of antipsychotic agents.

Discussion.

The results of this study suggest that olanzapine may be a useful agent for the treatment of drug-induced psychosis in nondemented patients with PD. The psychotic effects of dopaminomimetic medication, assessed by means of the BPRS, decreased significantly during treatment with olanzapine; in particular, the subscore of the core symptoms consisting of conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content decreased by 77%. The antipsychotic effect persisted even when the dose of dopaminomimetic agents was increased; indeed, there was a further fall in BPRS total score and core symptom subscore. The UPDRS total score as well as the ADL and motor symptoms subscores did not change during olanzapine treatment, but decreased significantly after dopaminomimetic challenge. Thus, in contrast to typical antipsychotics, the improvement in psychotic symptoms was not achieved at the cost of increased extrapyramidal manifestations.

In conclusion, olanzapine appears to be effective and well tolerated in the treatment of drug-induced psychosis in nondemented parkinsonian patients. Since psychosis is an important predictor of disease progression, ^[9] severely impairs quality of life, and is a frequent cause of admission to nursing homes, ^[10] this approach may have an important place in the management of PD.

Acknowledgment

The authors gratefully acknowledge the contribution of Mrs. Nicole Lodder.